Resistance to chemotherapy represents a major obstacle in breast cancer treatment. GRP78 is a protein upregulated in malignant but not benign human breast tumors, and is associated with resistance to chemotherapy in breast cancer patients. While it has been shown that this resistance depends on the BH3-only protein BIK, the mechanism of interaction between GRP78 and BIK still remains to be elucidated. Investigating the nature of this interaction, we discovered that deletion of the BH3-only domain in BIK results in altered protein interactions in 293T cells. Characterization of MCF-7/BUS human breast cancer cell clones that were resistant to estrogen-starvation therapy showed markedly elevated levels of GRP94. Knockdown of GRP94 by small interfering RNA in these resistant clones led to an increase in cell death. Resistance to chemotherapy is also a characteristic of cancer stem cells so we characterized molecular markers of putative breast cancer stem cells. Our results showed a minor putative breast cancer stem cell population in lymph node occult micrometastases. Overall these results help elucidate molecular characteristics that contribute to chemoresistance and that may serve as valuable targets for therapy, as well as help delineate molecular mechanisms contributing to estrogen-starvation therapy resistance in breast cancer.
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